tbuckley/cabot-search huggingface dataset:
Abstract 1307: The effect of circulating CXCL10 on osteosarcoma metastasis using orthotopic xenograft mouse models
Authors: Xiang Chen, Margaret Clement, John Hicks, Tsz Kwong Man
Journal: Cancer Research (2023)

Abstract Osteosarcoma is the most common malignant bone tumor in children. Despite the use of chemotherapy and surgery, the survival of patients with metastasis is still dismal. We have previously reported that a high serum level of CXCL10 is associated with a poor prognosis and metastasis in osteosarcoma, suggesting that the chemokine may affect the development of metastasis. Nonetheless, the effect of endocrine signaling of CXCL10 is largely unknown. It is unclear if the prognostic effect of circulating CXCL10 is due to its metastasis-promoting effect or if CXCL10 is merely a biomarker. In this study, we employed orthotopic xenograft mouse models to examine the effect of circulating CXCL10 with respect to metastasis. We first injected luciferase-labeled 143B osteosarcoma cells into the tibia of NOD/SCID mice to generate an orthotopic xenograft mouse model. When the tumor was detectable by bioluminescence, we injected 1.5ug of CXCL10 protein or saline intravenously via the tail vein every day for two weeks. The development of pulmonary metastasis was monitored by bioluminescence. The mice were sacrificed at the endpoint when bioluminescence was detected in the lungs. The mouse lungs were then resected and examined by H&amp;E staining for the detection of metastatic nodules. The mice in the experimental and control groups that developed lung metastases were compared. The results showed that no significant difference was observed between the two groups. The experiment was repeated one more time and similar results were observed. To investigate the influence of the cell line background, we analyzed another osteosarcoma cell line, MG63.3. No significant difference in metastasis development was observed between the mice injected with CXCL10 and the mice injected with saline. The results indicate that a higher level of circulating CXCL10 alone was not sufficient to promote pulmonary metastases in the orthotopic xenograft mouse models. We also showed that AKT phosphorylation was upregulated in the osteosarcoma cell lines incubated with CXCL10, ruling out that the CXCL10 protein used was biologically inactive. In summary, our results suggest that although an increased circulating level of CXCL10 is associated with a poor prognosis in osteosarcoma patients, it does not promote the development of pulmonary metastasis in xenograft mouse models. Circulating CXCL10 may only act as a prognostic biomarker, but not a metastatic driver. Alternatively, the CXCL10-CXCR3 axis may be necessary, but not sufficient, to cause metastasis. Citation Format: Xiang Chen, Margaret Clement, John Hicks, Tsz Kwong Man. The effect of circulating CXCL10 on osteosarcoma metastasis using orthotopic xenograft mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1307.
Abstract 5681: Tetra-specific antibody GNC-038: guidance and navigation gontrol (GNC) molecule development for treatment of CD19+ malignancies
Authors: Jahan Salar Khalili, Sa Xiao, Yi Zhu
Journal: Cancer Research (2023)

Abstract B cell malignancies treated with CD19-directed immunotherapies can relapse, in some cases due to clonal selection for reduced CD19 antigen expression or enhancement of immunosuppressive phenotypes. Here we demonstrate that a Guidance and Navigation Control (GNC) tetra-specific antibody, GNC-038, binds to CD19, CD3, PD-L1, and 4-1BB and mediates cytolysis of human leukemia and lymphoma cells by T cells. Redirected T cell cytolysis (RTCC) occurs in the presence of GNC-038 (Emfizatamab), resulting in the killing of CD19+ leukemia and lymphoma cell lines. The cytolytic functions induced by GNC-038 are similar to Blinatumomab in vitro, as indicated by T cell degranulation and production of IFN-gamma. Human T cells in PBMC exposed to GNC-038 in vitro proliferate in a dose-dependent fashion. Proliferation is further enhanced upon rechallenge with leukemic target cells. Proliferation of T cells from individuals with higher % PD-1+ and Effector polarized compartments is enhanced by GNC-038 compared to Blinatumomab. To evaluate the contribution of each binding domain of GNC-038 in mediating RTCC function, versions of GNC-038 were prepared, replacing each antigen binding domain with anti-FITC binding domains. Under assay conditions using PBMC for RTCC toward the CD19+ target cell line Nalm-6, the results demonstrate the contribution of each domain to the overall, anti-leukemic cytolytic activity. To evaluate the potential for GNC-038 to mediate cytokine release syndrome, the molecule is evaluated in soluble, and plate bound formats in the presence of PBMC and CD19+ leukemic targets cells. In comparison to Blinatumomab, the production of cytokines is comparable, with some notable differences. PBMC exposed to soluble GNC-038 for 48 hours produced more IFN-γ, IL-2 and TNF-α, while showing no significant difference in production of IL-6. Based on these results, the primary indicator of CRS, IL-6, does not suggest increased risk compared to Blinatumomab, while the type of T cell activity induced by GNC-038 in PBMC with leukemia cells is distinct. Collectively, the GNC-038 represents a class of multi-specific and multi-modal immune cell engagers with potential to mediate CD19+ cancer killing, while also increasing the T cell compartment’s therapeutic potential to respond to T cell redirection upon subsequent cycles of therapy. The clinical phase I-b study of GNC-038 is under way and the available data exhibit strong signals of efficacy with acceptable tolerability. Citation Format: Jahan Salar Khalili, Sa Xiao, Yi Zhu. Tetra-specific antibody GNC-038: guidance and navigation gontrol (GNC) molecule development for treatment of CD19+ malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5681.
Abstract 1198: T cell receptor (TCR) landscape of childhood brain tumors
Authors: Itay Raphael, Michal Nisnboym, Rebecca A. Raphael, Shikhar Uttam, Ian F. Pollack, Maria Chikina, Dhivyaa Rajasundaram, Gary Kohanbash
Journal: Cancer Research (2023)

Abstract T lymphocytes have a unique ability to recognize a vast array of antigens prompt by an enormous T cell receptor (TCR) repertoire. Characterization of tumor-infiltrating T cells (TILs) is key to understand MHC-restricted anti-tumor immunity and for developing T cell-centered immunotherapies such as adoptive cell therapy and tumor vaccines. In the current work, we investigated RNA-Seq data from 997 pediatric brain tumor patients and performed a large-scale comprehensive examination of the immunogenomic and TCR landscape of TILs across the entire spectrum of pediatric brain tumors. We show that the relative ratio between T cell clonal diversity and T cell abundance within each sample, represented by the clonal expansion index (CEI), is a strong predictor of prognosis both within and between tumor types. Interestingly, we show that CEI is strongly associated with molecular subgroups of medulloblastoma but not with known genomic features of these subgroups. Investigation of TCR clonotypes recognizing a common recurrent tumor-antigen across patients based on CDR3 homology and characteristics, reveals 9 TCR clusters which are tumor-type restricted with defined prognoses and HLA dominance. Using computational immunogenomics and machine learning-based investigations of these clusters we identified novel putative HLA-restricted tumor antigens which could bind and activate the clusters’ specific TCRs. Importantly, our framework grounded the foundations for developing a precision medicine approach of T cell-centered immunotherapies. These findings have major implications for understanding the interplay between T cell and tumor genomics, and for developing new immunotherapies for children with brain tumors and other cancers. Citation Format: Itay Raphael, Michal Nisnboym, Rebecca A. Raphael, Shikhar Uttam, Ian F. Pollack, Maria Chikina, Dhivyaa Rajasundaram, Gary Kohanbash. T cell receptor (TCR) landscape of childhood brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1198.
Abstract 1690: Myc suppression permits entry into the cancer endocycle to evade toxic effects of chemotherapy
Authors: Michael Loycano, Kenneth J. Pienta, Sarah R. Amend
Journal: Cancer Research (2023)

Abstract Recent advances in precision medicine and immunotherapy have made great strides in cancer treatment and care, but chemoresistance remains a major challenge. One method of chemoresistance employed by cancer cells is accession of the protective polyaneuploid cancer cell (PACC) state, in which cells enter a functionally dormant state upon environmental stress. Entry into the PACC state begins with a whole-genome duplication event followed by endocycling, where the cells are metabolically active and cycling through repeated G1, S and G2 phases of the cell cycle without dividing. While in this state, cells avoid the mitotic stress exerted by common chemotherapeutics and survive therapy, eventually undergoing a depolyploidization process to repopulate the tumor, driving cancer lethality. The mechanisms by which a cancer cell can switch between a mitotic cell cycle and an endocycle are unknown. Cancer is characterized by deregulated cell proliferation, often driven by mutation or amplification of genes that govern the cell cycle. C-myc, an oncogenic transcription factor, is dysregulated in roughly 70% of cancers and is clinically used as a negative prognostic factor for disease-free survival and metastasis. C-myc is responsible for the transcriptional activation of many cell cycle-related genes, and repression of cell cycle inhibitors. Our data indicate that endocycling cells in the PACC state downregulate c-myc expression. Transcriptomic analyses show repression of myc targets, along with supporting protein data that total c-myc protein levels are decreased. While myc downregulation is expected in non-proliferative cells, the compensatory mechanisms mediating the G1/S transition in the cancer endocycle remain unknown. These observations suggest the presence of underlying mechanisms to reprogram the mitotic cell cycle to access the PACC state. We hypothesize that myc downregulation is essential for cells to activate the cancer endocyle and enter the protective PACC state. Understanding the mechanisms that govern this transition is crucial to generate next-generation cancer therapeutics to block accession or disrupt this state. Citation Format: Michael Loycano, Kenneth J. Pienta, Sarah R. Amend. Myc suppression permits entry into the cancer endocycle to evade toxic effects of chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1690.
Abstract 6361: A preclinical model of acquired anti-PD-1 resistance is responsive to SEA-TGT, an effector-function enhanced anti-TIGIT monoclonal antibody
Authors: David R. Gruber, Weiping Zeng, Bob Thurman, Brian P. O'Connor, Shyra J. Gardai, Alyson J. Smith
Journal: Cancer Research (2023)

Abstract Immune checkpoint inhibitors, including monoclonal antibodies targeting the PD-1/PD-L1 axis, induce robust antitumor immunity in a subset of patients with various cancers. Despite continued success of these therapies, some patients experience limited efficacy owing to clinically complex and unresolved mechanisms of primary and acquired immunotherapy resistance. To begin to understand the mechanisms of acquired resistance to anti-PD-1 blockade, we developed a syngeneic murine CT26 colorectal tumor model that is resistant to anti-PD-1 therapy. To achieve this, CT26 tumors were subjected to successive rounds of increasing levels of anti-PD-1 therapy. When tumors grew out, they were cultured in vitro and then re-implanted and re-treated for three rounds until PD-1 resistance was achieved. To characterize the underlying drivers of acquired resistance across the generation of the model, wild type and anti-PD-1 resistant tumors and cultured cell lines were evaluated by flow cytometric immunophenotyping and RNA-sequencing analysis. To assess how observed changes in the tumor microenvironment impact response to various therapeutics, the resistant tumors were treated with anti-PD-1 therapy or SEA-TGT, a nonfucosylated anti-TIGIT mAb with enhanced Fc-function that drives activity through multiple modes of action. As expected, treatment with anti-PD-1 monotherapy was ineffective, however, treatment with SEA-TGT demonstrated potent anti-tumor activity. These data are consistent with responsiveness to anti-TIGIT agents in other in vivo models of PD-1 resistance and/or PD-1 refractory response, indicating that the factors driving resistance to anti-PD-1 therapy can be different than those driving response to other known checkpoint molecules such as TIGIT. Thus, investigational agents such as SEA-TGT may have the potential to be efficacious in tumors that are primary or secondarily resistant to anti-PD-1 therapy. We have initiated a phase 1 study (NCT04254107) evaluating the safety, tolerability, and activity of SEA-TGT monotherapy and in combination with anti-PD-1 therapy in patients with advanced malignancies. Citation Format: David R. Gruber, Weiping Zeng, Bob Thurman, Brian P. O'Connor, Shyra J. Gardai, Alyson J. Smith. A preclinical model of acquired anti-PD-1 resistance is responsive to SEA-TGT, an effector-function enhanced anti-TIGIT monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6361.
Abstract 5663: Discovery and characterization of anti-LILRB2 antibody SPX-104
Authors: Anthony Haight, Qian Chen, Ernesto Rodriguez, Martin Siekierzycki, Victoria Hall, Brandon Williams, Jun Shi, Dinh-Duc Nguyen, Robert Cai, Jichun Ma, Michael White, Jingdong Qin, Jadon Shen, Chuanke Zhao, Zhuona Rong, Lin Meng, Chengchao Shou
Journal: Cancer Research (2023)

Abstract T-cell based immunotherapies have produced durable remission in certain cancer patients, but owing at least partially to immunosuppression in the tumor microenvironment, response rates with current therapies remains challenging. Reversing the immunosuppression is a recognized pathway for enhancing the activity of existing IO therapies. LILRB2 (ILT4) is a key receptor for macrophage maturation and polarization and an emerging therapeutic target in immuno-oncology. This research aims to produce anti-LILRB2 antibodies to redirect the polarization of myeloid cells, specifically macrophages, in the tumor microenvironment. The LILRB2 antibodies were generated through the mouse hybridoma method. After humanization and maturation, potent and selective IgG4 anti-LILRB2 antibodies were obtained. Binding affinities were evaluated through ELISA and 293T-LILRB2 cell flow cytometry binding assays which demonstrated sub-nanomolar binding affinity as well as effective blocking of the interaction of LILRB2 with its ligands HLA-G and HLA-A2 for multiple antibodies. SPX-104 was shown to redirect macrophage polarization in primary cultured human PBMC and human monocyte derived macrophage (HMDM) models. SPX-104 treatment induced hTNFa expression and suppressed hIL10 expression in the LPS stimulated PBMC model. In the HMDM model, SPX-104 effectively induced pro-inflammatory cytokine hTNFα expression in M-CSF. Furthermore, an autologous mixed lymphocyte reaction (auto-MLR) assay to evaluate T cell response showed dose-dependent increases in hIFNγ and hGM-CSF expression following SPX-104 treatment. In a CD34-humanized hLILRB2 transgenic mouse efficacy model, SPX-104 in combination with an immune checkpoint inhibitor, effectively inhibited tumor growth. These results confirm enhanced T cell activity following macrophage redirected polarization. The in vitro and in vivo evaluation, of SPX-104 relative to other anti-LILRB2 antibodies will be presented. Citation Format: Anthony Haight, Qian Chen, Ernesto Rodriguez, Martin Siekierzycki, Victoria Hall, Brandon Williams, Jun Shi, Dinh-Duc Nguyen, Robert Cai, Jichun Ma, Michael White, Jingdong Qin, Jadon Shen, Chuanke Zhao, Zhuona Rong, Lin Meng, Chengchao Shou. Discovery and characterization of anti-LILRB2 antibody SPX-104. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5663.
Abstract 4166: Effects of cyproheptadine in eliciting natural killer cell-mediated immune response in bladder cancer
Authors: Himani Kumari, Guan-Ling Lin, Chih-Chieh Yeh, Ciao-Ni Chen, Yu-Ming Chuang, Wan-Hong Huang, Wen-Long Huang, Steven Lin, Michael W. Chan
Journal: Cancer Research (2023)

Abstract Bladder cancer is one of the most common occurring cancers in urothelial carcinoma. The previous study suggested that cancer cells undergo immunoevasion due to epigenetic silencing of NKG2DL, in which NKG2D-NKG2DL interaction induced natural killer (NK) cell-mediated cytotoxicity. We hypothesized that NK-mediated cytotoxicity can be reactivated by restoring the expression of NKG2DL on tumor cells. Our previous studies demonstrated that cyproheptadine (CPH) is a novel HDAC inhibitor exhibiting antitumor activity by cell cycle arrest and apoptosis. To understand the mechanism behind, RNA-seq showed an upregulation of ULBP2, a NKG2DL, in bladder cancer cells treated with CPH. Interestingly, upregulation of ULBP2, was accompanied with the enrichment of H3K27Ac and H3K4me3 at ULBP2 promoter, was observed in cells treated with CPH. Increased NK-specific lysis was observed in CPH-treated cells co-cultured with NK-92 cells. More importantly, treatment of CPH enhanced the efficacy of immune checkpoint inhibitor in a syngeneic mice bladder cancer model. In conclusion, our results suggested that CPH may be a novel HDAC inhibitor which may elicit immune response in NK-cell dependent manner. Citation Format: Himani Kumari, Guan-Ling Lin, Chih-Chieh Yeh, Ciao-Ni Chen, Yu-Ming Chuang, Wan-Hong Huang, Wen-Long Huang, Steven Lin, Michael W. Chan. Effects of cyproheptadine in eliciting natural killer cell-mediated immune response in bladder cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4166.
Abstract 416: Phosphorylation of CDK9 transduces ALK signaling to promote resistance to PARP inhibitors via RNA Pol II activated homologous recombination repair
Authors: Yu-Yi Chu, Jianjun Gao, Dihua Yu, Mien-Chie Hung
Journal: Cancer Research (2023)

Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are currently the most promising drugs to induce synthetic lethality in tumor with homologous recombination (HR) deficiency. However, development of resistance to PARPi is an almost universal occurrence in tumor despite initial sensitivity. Additionally, how to identify the right patients for PARPi monotherapy or in combination with other agents remains a substantial clinical challenge. Therefore, understanding the molecular underpinnings of PARPi resistance is critical to the development of rational combinatorial treatment strategies and identification of novel biomarkers which will in turn facilitate optimization of outcomes for patients receiving PARPi. By employing a screening procedure using phospho-RTK antibody array, our study identifies phosphorylated ALK (p-ALK) expression is higher in PARPi/platinum resistant cells relative to sensitive cells. We further demonstrate that p-ALK expression in human ovarian cancer tissue is associated with resistance to PARPi and platinum-based chemotherapy. Notably, FDA approved ALK inhibitors induce an HR-deficient phenotype and sensitize PARPi/platinum-resistant tumors to PARPi in vitro and in vivo. Mechanistically, ALK contributes to PARPi resistance by tyrosine phosphorylating CDK9 at Y19, thereby increasing the protein stability and kinase activity of CDK9 which in turn stabilizes positive transcriptional elongation factor b (P-TEFb) to activate RNA pol II and turn on HR repair genes transcription. Importantly, the phosphorylated counterparts of ALK/CDK9 complex (p-ALK/p-Y19 CDK9) can serve as a biomarker to identify patients with PARPi/platinum-resistant tumors which most likely to respond to dual PARP and ALK inhibition. Together, our findings identify p-ALK/p-Y19-CDK9 mediated stabilization of P-TEFb as a critical mechanism of PARPi resistance and supports a biomarker-guided therapeutic strategy combining ALKi and PARPi to induce synthetic lethality. Citation Format: Yu-Yi Chu, Jianjun Gao, Dihua Yu, Mien-Chie Hung. Phosphorylation of CDK9 transduces ALK signaling to promote resistance to PARP inhibitors via RNA Pol II activated homologous recombination repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 416.